Infection with oncogenic types of human papillomavirus (HPV) predisposes to neoplasia. Certain oncogenic HPVs, including HPV8, are associated with human skin cancer. The ability of HPV8 to induce skin cancer was demonstrated experimentally by Herbert Pfister using a K14-HPV8 transgenic mouse model. Skin cancer is the major complication of organ transplantation. It also is unusually common among AIDS patients, strongly indicating an infectious etiology. As 100,000 people in the U.S. are living with organ transplants and 1,000,000 with AIDS, skin cancer is a significant medical problem. The importance of AIDS-related cancers worldwide cannot be overstated. The hypothesis of this proposal is that Langerhans cells (LCs) govern HPV persistence and associated malignant progression. Until lately LCs have mainly been regarded as stimulators of adaptive immunity. This notion has been recently been challenged by Daniel Kaplan at Yale who showed that LC-deficient transgenic mice developed exaggerated contact hypersensitivity responses (CHS), demonstrating surprisingly that LCs downregulated CHS responses. Very recent studies demonstrated that the LC- deficient mice were unexpectedly protected against the development of chemically induced tumors (see Preliminary Studies). Thus during chemical carcinogenesis as well as CHS, LCs downregulated adaptive immunity. We propose to rigorously test the role of LCs in the development of HPV8-associated cutaneous malignancy using LC-deficient transgenic mice, K14-HPV8 transgenic mice and a novel HPV8 transgenic mouse model designed to provide tight temporal, spatial and dynamic control over transgene expression. The Specific Aims will test whether LCs inhibit or enhance the rejection/maintenance of HPV transgenic skin grafts (as a model of subclinical infection) and/or HPV8-associated tumorigenesis. If the results demonstrate that LCs enhance HPV8-mediated tumorigenicity, they would imply a major paradigm shift in our understanding of this tumor type. Ultimately, the information would provide novel approaches for the prevention and treatment of HPV-associated cancers in high-risk individuals. PUBLIC HEALTH RELEVANCE: Human papillomavirus (HPV) infections can lead to the development of squamous cell carciomas although carcinoma is a rare outcome of infection. We hypothesize that Langerhans cells, a type of immune cell, facilitate HPV persistence and malignant progression by downregulating the development of benefical immune responses. If the results of this investigation substantiate our hypothesis, they will provide new insight into the regulation of HPV pathogenesis as well as novel targets for the development of immune-based strategies of direct clinical benefit to patients at high-risk of developing HPV-associated cancers.